This invention concerns a polymeric delivery system for the controlled and continuous administration of therapeutically effective amounts of LHRH analogs. More specifically, the invention relates to implantable silicone elastomer matrix systems which provide substantially constant and prolonged administration of therapeutically effective amounts of a luteinizing hormone-releasing hormone (LHRH) analog.
Continuous chronic administration of LHRH agonist and antagonist analogs has been found to block the secretion of gonadotropins in both male and female animals, thereby suppressing the production of gonadal steroids and gametes. As a result, such LHRH analogs have been indicated for controlling fertility, suppressing sexual behaviour in animals, causing regression of endometriotic lesions and prostatic cancers, and in the treatment of precocious puberty.
Conventional administration of LHRH analogs includes subcutaneous and intramuscular injections, and less commonly intranasal administration. Oral administration is impossible because the drugs are inactivated in the gastrointestinal tract. However, because LHRH analogs have short therapeutic half-lives ranging from several seconds to a few hours, frequent injections are necessary to achieve therapeusis, rendering chronic administration difficult and costly. A more useful approach is the implantation or other in situ application of long acting controlled release systems. In this way, active LHRH analog can be continuously delivered at therapeutic rates for prolonged periods without the necessity of daily or more frequent injections.
Diffusional matrix systems as devices for continuous drug administration in situ have significant commercial advantages in their ease and cost of manufacture when compared to other implantable drug delivery systems such as membrane controlled reservoir devices. Additionally, matrix type systems are one of the only means of achieving continuous controlled administration of macromolecular polypeptides, which do not diffuse readily across most polymeric membranes.
Langer et al. have demonstrated that macromolecules such as large polypeptides can be continuously released from ethylene vinyl acetate copolymer (EVA) matrices via diffusion through pores which are created in the matrix as the water-soluble particles of polypeptide are dissolved by incoming fluids. (See U.S. Pat. No. 4,391,797; Nature, Vol. 263, 797-799 (1976); Journal or Pharmaceutical Sciences, Vol. 69, No. 3, 265-270 (1980); Journal of Membrane Science, Vol. 7, 333-350 (1980); Journal of Pharmaceutical Sciences, Vol. 72, No. 10, 1181-1185 (1983); and Journal of Controlled Release, Vol. 1, 259-267 (1985)). However, the release rate of macromolecules from these systems has been shown to decrease with time, following (time).sup.-1/2 kinetics. Methods which have been implemented to achieve more nearly zero-order release with these systems include application of a thin membrane coating on all surfaces, covering all but a single surface with an impermeable material, and constructing the device so that only the surface from which release takes place is an inwardly releasing hemisphere (See, for example, "A New Approach to Achieve Zero--Order Release Kinetics From Diffusion--Controlled Polymer Matrix Systems" by Rhine et al. in Controlled Release of Bioactive Materials, R. Baker, Ed., Acacemic Press 1980).
Silicone elastomers have been used in both membrane controlled and matrix-type drug delivery systems for controlled administration of small, relatively water-insoluble molecules such as norgestrel, norethindrone, megestrol acetate and estradiol. The advantages of the silicone elastomers for parenteral in situ drug delivery include their long term proven biocompatibility, and their ease and low cost of fabrication. Curing can take place at room temperature, and organic solvents are not required. A perceived disadvantage however, has been their low permeability to water-soluble and large molecules.
Recently, Hsieh et al. described silicone elastomer matrices which released bovine serum albumin and other macromolecular polypeptides at a nearly constant rate in vitro for more than 100 days. (See Pharmaceutical Technology, June 1985, 39-48). However, to achieve a constant rate of release, these systems were encapsulated in an impermeable plastic (polyethylene or silicone rubber) tube which was coated at one end with an impermeable material, thus permitting release of drug from only the single circular surface at the open end of the tube, rather than from all surfaces of the matrix.
The formulation of LHRH analogs in matrix systems for long term drug delivery is particularly challenging because of their extremely high water-solubilities and potencies. Yet because of their high potencies, and their mechanism of action on the delicately balanced endocrine system, it is highly desirable that the rate of release achieved by such a system be constant as well as controlled. Implantable systems capable of controlled release of an LHRH analog for one month have been developed using a biodegradeable poly(lactide-co-glycolide) matrix in the form of microcapsules and larger implants. (See U.S. patent application Ser. No. 699,715 filed Feb. 8, 1985 and now U.S. Pat. No. 4,675,797 and EP Application No. 82300416. These systems operate by a combination of erosion and diffusion. However, they generally require the use of an organic solvent in fabrication. Additionally, they cannot be readily removed from the animal except during the very early period following implantation.
Thus, there is a need for a biocompatible delivery system capable of delivering therapeutic levels of LHRH analogs at constant rates for prolonged periods of time. Such a system should be a readily manufacturable monolithic device, without the additional requirements of impermeable coatings, membranes, microencapsulation and/or specialized device geometry.